Method for the synthesis and purification of ethers

ABSTRACT

Methods of synthesizing and purifying ethers are described. The synthesis and purification are achieved using an etherification technique followed by one or two fractional distillations. The etherification utilizes an element having low work function properties. Examples of low work function elements include, but are not limited to, metals or their hydrides, such as sodium, lithium or potassium or some combination thereof. This technique yields ethers of greater than 90% purity.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The invention described herein may be manufactured and used by or forthe government of the United States of America for governmental purposeswithout the payment of any royalties thereon or therefor.

FIELD OF THE INVENTION

The invention generally relates to the synthesis and purification ofethers.

BACKGROUND OF THE INVENTION

Ethers are an important raw material, solvent, and intermediate used inorganic synthesis, as oxygenators for fuels, as diesel fuel additives,in pharmaceuticals, in agrochemicals, in refrigeration applications, asflavoring agents, and in many other applications.

A number of scientific publications and patents have studied, orproposed, the use of alkyl tetrahydrofurfuryl ethers, for example, for adiverse array of applications. In 1930, Kirner synthesized a smalllibrary of alkyl tetrahydrofurfuryl ethers, and analyzed their use as ananesthetic and their toxicity in mice and guinea pigs. W. R. Kirner,Alpha-Tetrahydrofurfuryl Chloride and Alpha-Tetrahydrofurfuryl Ethers,Journal of the American Chemical Society, 1930, 52, 3251. Some publishedworks show the utility of these compounds as structural modifiers inrubbers. Modification of rubber with various alkyl tetrahydrofurfurylethers increases the static friction coefficient of the product.Additionally, these compounds have been proposed as components of heatpumps, paint strippers, and as fuel additives.

There is a large market for these compounds, and there are proposedmethods for their synthesis. For example, current syntheses of ethyltetrahydrofurfuryl ether (ETFE) are described in U.S. Pat. No. 4,305,878to Chu, et al. The method disclosed in the Chu et al. patent describesthe purification of ETFE via multiple extractions using multiple calciumchloride and other aqueous salts, followed by fractional distillation.Chu specifically states the difficulty in separating ETFE fromtetrahydrofurfuryl alcohol (THFA) and alcohol using distillation andthat multiple aqueous extractions were required to remove THFA to belowacceptable levels. This requirement for multiple extractions anddistillations is both inefficient and undesirable.

Cao, et al., “Solid acid-catalyzed conversion of furfuryl alcohol toalkyl tetrahydrofurfuryl ether”, 2015, Catalysis Communications, Volume58, Pages 76-79) disclose a cumbersome process which uses at least two(2) separate catalytic steps with low yields (ETFE—40.6% [at 55° C.])and low purity.

One tetrahydrofurfuryl ether that has been cited as difficult to obtainis bis(tetrahydrofurfuryl) ether (BTHFE). The one previous report of itssynthesis lacked an in-depth characterization of the compound, leavingsome doubt as to the true identity of the reported product. L. M.Prutkov, I. K. Sanin, I. V. Kamenskii, Bis(tetrahydrofurfuryl) ether,Khim. Geterotsikl. Soedin, 632 (1966).

The current invention provides novel synthesis and purificationtechniques in which no extractions are necessary, and in which at least90% purity, and greater than 98% purity ether has been obtained in oneor two steps using fractional distillation in the presence of an excessof a reactive element. This method is particularly useful for thesynthesis and purification of tetrahydrofurfuryl ethers, such as alkyltetrahydrofurfuryl and bis(tetrahydrofurfuryl) ethers.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not to be viewed as being restrictive of the invention, as claimed.Further advantages of this invention will be apparent after a review ofthe following detailed description of the disclosed embodiments.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the synthesis and purification ofethers, preferred ethers include alkyl tetrahydrofurfuryl ethers (TFE),for example, ethyl tetrahydrofurfuryl ether (ETFE) having the formula:

and

bis(tetrahydrofurfuryl) ethers (BTHFE) having the formula:

In the method of the present invention tetrahydrofurfuryl alcohol (THFA)is mixed with up to about a molar equivalent amount of a source of a lowwork function element. After the reaction of THFA with the low workfunction element is complete, a halide is added drop wise and thereaction mixture is heated overnight under inert gas. The resultingmixture is fractionally distilled with all distillate collected in aflask. This first distillate is found to have a roughly 50/50 mixture ofTHFA and a tetrahydrofurfuryl ether. The distillate is then reacted(with heating) with sufficient low work function element (which can bethe same or different than the low work function element previouslyused), until all of the THFA is reacted—this is evidenced by thepresence of unreacted low work function element. This distillatecontaining the unreacted low work function element is then fractionallydistilled; the distillate is shown to contain purifiedtetrahydrofurfuryl ether.

An alternative embodiment of the method involves the reaction of THFAwith approximately ½ equivalent of low work function element. After thereaction of THFA with the low work function element is complete, ½ anequivalent of a halide is added and the reaction mixture is heatedovernight under nitrogen. The remaining ½ of equivalent of low workfunction element and ½ equivalent of halide are then added and thereaction is heated overnight under nitrogen. When this reaction iscomplete, small amounts of low work function element are added untilunreacted low work function element is detected. This mixture is thenfractionally distilled and the collected distillate is shown to containpurified tetrahydrofurfuryl ether.

The work function of an element corresponds to the minimum amount ofenergy needed to remove an electron from the element (i.e., an electronfrom the highest filled level in the Fermi distribution of a solid sothat it is stationary at a point in a field-free zone just outside thesolid, at absolute zero). In metals, work function and ionization energyare the same.

Designated as φ, and presented in units of electron volts (eV),preferred low work function elements for the present invention have a φvalue of less than about 3.0 eV. Such elements include, but are notlimited to: barium (φ=2.52−2.7 eV), calcium (φ=2.87 eV), cerium (φ=2.9eV), cesium (φ=2.14 eV), europium (φ=2.5 eV), gadolinium (φ=2.90 eV),potassium (φ=2.29 eV), lithium (φ=2.9 eV), sodium (φ=2.36 eV), rubidium(φ=2.261 eV), samarium (φ=2.7 eV), strontium (φ=˜2.59 eV), and ytterbium(φ=2.6 eV).

Preferred sources of low work function elements are metals and metalhydrides. A preferred low work function element is a reducing agent.Examples of preferred low work function elements include, but are notlimited to, elemental magnesium metal, lithium hydride, potassiumhydride, rubidium hydride, cesium hydride, magnesium hydride, andcalcium hydride. Sodium is a preferred low work function element due toits low cost, ready availability, ease of use, and high reactivity. Themethod of the invention can utilize one or more low work functionelements or combinations thereof.

Halides used in the method of the present invention can includefluorides, chlorides, bromides, iodides, or astatides, preferably abromide or chloride, more preferably a bromide. Halides have the formulaXR, where R can be a substituted or unsubstituted alkyl, alkenyl, oralkynyl of 1 to 20 carbon atoms, a substituted or unsubstitutedheterocycle, or a substituted or unsubstituted phenyl, preferably analkyl of from 1 to 10 carbon atoms and X is F, Cl, Br, I, or At.

In one preferred embodiment, ETFE is formed by the reaction oftetrahydrofurfuryl alcohol (THFA), ethyl chloride or ethyl bromide, andsodium hydride or sodium. In the method of the present inventiontetrahydrofurfuryl alcohol (THFA) is mixed with about a less than molarequivalent amount of sodium hydride or sodium. After the reaction ofTHFA with the sodium hydride or sodium is complete, ethyl chloride orethyl bromide is added drop wise and the reaction mixture is heatedovernight under inert gas. The resulting mixture is fractionallydistilled with all distillate boiling at around 158-162 degrees C.collected in a flask. This first distillate is found to have a roughly50/50 mixture of THFA and ethyl tetrahydrofurfuryl ether. The distillateis then reacted (with heating) with sufficient sodium hydride or sodium(which can be the same or different than previously used), until all theTHFA is reacted—this is evidenced by the presence of unreacted low workfunction element. This distillate containing the unreacted sodiumhydride or sodium is then fractionally distilled, collecting thematerial boiling between 154 and 158 degrees Celsius at 0.91 atmospherepressure, which is shown to contain purified ethyl tetrahydrofurfurylether.

EXAMPLES Example 1

220 mL (230.645 g, 2.26 moles) of tetrahydrofurfuryl alcohol was put ina 500 mL round bottom flask equipped with a stir bar and under nitrogengas at room temperature. 8.43 grams (0.37 moles) of sodium metal wasadded and the reaction was allowed to proceed to completion forming thesodium salt of tetrahydrofurfuryl oxide (C₅H₉O₂Na). The contents wereheated during the reaction to about 60 degrees C. to insure the mixtureremained liquid. A total of 27.25 mL (39.8 g, 0.37 moles) of ethylbromide was added dropwise over the course of several hours. Thereaction mixture was then heated to reflux overnight; boiling occurredat about 75 degrees C. The mixture was then fractionally distilled andall the material (about 40 grams) that boiled between 145 and 160degrees Celsius was collected. The distillate was then put in a 100 mLround bottom flask and sufficient sodium to react with any impuritieswas added, then a small excess of sodium was added. The presence ofmetallic sodium was used as an indication that an excess of sodium asadded. This material was fractionally distilled and the distillate thatboiled between 154 and 157 degrees Celsius at 0.91 atm pressure wascollected. The material, 16.4 grams (35% yield based upon limitingreactant sodium) was analyzed by Gas Chromatography/Mass Spectrometryand was found to be 99.8% pure (commercially purchased ETFE was found tobe 99.6% pure)

Example 2

100 mL (104 g, 1.01 moles) of tetrahydrofurfuryl alcohol was put in a500 mL round bottom flask equipped with a stir bar and under nitrogengas. 9.8 grams (0.43 moles) of sodium metal was added and the reactionwas allowed to proceed to completion. The contents were heated duringthe reaction between 50 and 80 degrees C. to insure the mixture remainedliquid. 32 mL (32.0 g, 0.29 moles) of ethyl bromide was added dropwiseover the course of several hours. The reaction mixture was then heatedto reflux overnight. The mixture was then fractionally distilled and allthe material (about 54.5 grams) that boiled between 145 and 160 degreesCelsius was collected. The distillate was then put in a 200 mL roundbottom flask and sufficient (7.5 grams, 0.33 moles) sodium to react withany impurities was added. The presence of metallic sodium was used as anindication that an excess of sodium as added. This material wasfractionally distilled and the fraction that boiled between 154 and 157degrees Celsius at 0.91 atm pressure was collected. The material, 30grams (52% based upon limiting reactant sodium and 30% based upon THFA)was analyzed by Gas Chromatography/Mass Spectrometry and was found to be99.7% pure.

The residue of the second distillation was then put into the residue ofthe first fractional distillation and the excess sodium was allowed tocompletely react. 24.5 mL (35.8 g, 0.33 moles) of ethyl bromide was thenadded dropwise over several hours, and then the reaction was heated toreflux for 12 hours. The mixture as cooled, an additional 2 grams ofsodium was added to provide excess sodium and this mixture wasfractionally distilled and the fraction that boiled between 154 and 157degrees Celsius at 0.91 atm pressure was collected (an additional 26grams) was collected. The product was analyzed by GasChromatography/Mass Spectrometry and found to be 99.7% pure. The overallyield based upon THFA was 56%.

Example 3

12.4 mL (13.0 g, 0.128 moles) of tetrahydrofurfuryl alcohol was put in a50 mL round bottom flask equipped with a stir bar and under nitrogengas. 1.4 grams (0.06 moles) of sodium metal was added, heated to between40 and 70 degrees C., and the reaction was allowed to proceed tocompletion. Ethyl bromide (5 mL, 7.3 g, 0.07 moles) was added drop-wiseover the course of several hours. The reaction was refluxed for severalhours. The reaction was cooled then an additional 1.4 grams (0.061moles) of sodium metal was added and the reaction was allowed to proceedto completion. An additional 5 mL (7.3 g, 0.031 moles) of ethyl bromidewas added drop-wise over the course of several hours. The mixture wascooled, and sufficient sodium was added (with careful heating undernitrogen) until unreacted sodium was detected. The mixture was thenfractionally distilled and the fraction that boiled between 154 and 157degrees Celsius at 0.91 atm pressure was collected (9.6 grams ofproduct). Chromatography/Mass Spectrometry and was found to be 99.6%pure (the commercially purchased ETFE was found to be 99.6% pure). Theoverall yield based upon THFA was 57%.

Example 4

20.0 mL (20.4 g 0.206 moles) of tetrahydrofurfuryl alcohol was put in a50 mL round bottom flask equipped with a stir bar and under nitrogengas. 4.8 grams (0.21 moles) of sodium metal was added and the reactionwas allowed to proceed to completion at a temperature between 40° and70° C. 22.5 mL (32.8 g, 0.30 moles) of ethyl bromide was added drop-wiseover the course of several hours. The reaction was refluxed for 3 days.The reaction was cooled then filtered. An additional 5 mL of ethylbromide was added drop-wise over the course of several hours. Themixture was cooled, and sufficient sodium was added (with carefulheating under nitrogen) until unreacted sodium was detected. The mixturewas then fractionally distilled under low pressure and the fraction thatboiled between 154 and 157 degrees Celsius at 0.13 atm pressure wascollected 9.6 grams of product was collected. Chromatography/MassSpectrometry and was found to be 99.6% pure (the commercially purchasedETFE was found to be 99.6% pure). The overall yield based upon THFA was57%.

Example 5

Synthesis of 2-Methanesulfonylmethyltetrahydrofuran

A 3-neck round bottom flask was filled with 200 mL pyridine and 88 mL(91.8 g, 0.90 moles) of THFA. An addition funnel was added, the mixturewas placed in an ice/water bath, and purged with nitrogen for 1 hour.Methanesulfonyl chloride (73 mL, 108.4 g, 0.94 moles) was added dropwise to the continuously chilled mixture over 12 hours. The mixture wasthen allowed to warm to room temperature over the next 48 hours, atwhich time it was combined with 500 mL of 1.2 M HCl, and extracted threetimes with 125 mL portions of dichloromethane. The organic phases werecombined and then extracted once with 125 mL of 1.2 M HCl, followed by125 mL of saturated NaCl. Finally, the dichloromethane solution wasdried with MgSO4, and the solvent was removed under reduced pressure.The crude product was a light yellow liquid, and the yield of crudematerial was 144 grams (89%). Portions of the crude material were vacuumdistilled at 0.34 mmHg to obtain pure product, which was a clear,colorless liquid. This material was characterized by 1H and 13C NMR, 2-DNMR, GC/Mass Spectrometry, Infrared Spectroscopy, and elementalanalysis. 1H NMR: 1.60 m (1H); 1.8 m (2H); 1.9 m (1H); 3.03 s, (3H);3.76 m (2H); 4.0 m (2H); 4.14 m (1H). 13C NMR: 76.29, 71.65, 68.60,37.55, 27.60, 25.75. Elemental Analysis: Calculated: 39.93% C; 6.71% H;17.79% S. Found: 40.1% C; 6.7% H; 18:01% S. GC/MS indicates 98.6%purity.

Synthesis of bis(tetrahydrofurfuryl) ether

A 2-neck round bottom flask was filled with 25 mL of THF and 8.36 g(0.67 moles) of the sodium salt of THFA, which was prepared by addingsodium metal to excess THFA, and collecting the resulting solid. Themixture was placed under a nitrogen flow, heated to approximately 70degrees Celsius using an oil bath, and 12.1 g (0.74 moles) of2-methanesulfonylmethyltetrahydrofuran was added drop wise over thecourse of several hours. Then, the temperature of the oil was raised toapproximately 170 degrees Celsius, and the THF was allowed to evaporatewhile the progress of the reaction was monitored by removing smallaliquots from the mixture and recording the NMR spectrum. The mixturewas allowed to cool to room temperature when the NMR spectrum indicatedthat the reaction was approximately 90% complete (after roughly 48hours). Diethyl ether (100 mL) was added to the room temperaturemixture, which was then filtered, and the ether was removed by rotaryevaporation. Yield of crude material, which was a brown colored liquid,was 8.25 g. The crude material was purified by vacuum distillation, andtemperature of the distillate was 48 degrees Celsius at 0.43 mmHg. Thismaterial was found to be approximately 99% pure by GC-MS. ElementalAnalysis: Calculated: 64.48% C; 9.74% H; 25.75% O. Found: 63.71% C;9.89% H; 26.4% O.

It is to be understood that the foregoing examples are exemplary andexplanatory only and are not to be viewed as being restrictive of theinvention, as claimed. The present invention is not limited to theproduction and purification of ETFE. The present processes and methodscan be used to make and purify any type of ether by one skilled in theart and, as such, does not invalidate the spirit and method of theinvention.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

While the invention has been described, disclosed, illustrated and shownin various terms of certain embodiments or modifications which it haspresumed in practice, the scope of the invention is not intended to be,nor should it be deemed to be, limited thereby and such othermodifications or embodiments as may be suggested by the teachings hereinare particularly reserved especially as they fall within the breadth andscope of the claims here appended.

What is claimed:
 1. A method of synthesizing and purifying an ether,comprising: reacting a mixture of tetrahydrofurfuryl alcohol and up toabout one equivalent of at least one low work function element; reactingsaid mixture with a halide; fractionally distilling said reacted mixtureto yield a first distillate; reacting said first distillate with anexcess amount of at least one low work function element; and,fractionally distilling said reacted first distillate to obtain thepurified ether wherein said at least one low work function element is anelemental metal or a metal hydride which has a φ of less than about 3.0eV.
 2. The method according to claim 1 wherein said low work functionelement is selected from the group consisting of elemental sodium metal,elemental lithium metal, elemental potassium metal, elemental rubidiummetal, elemental cesium metal, elemental magnesium metal, elementalcalcium metal, sodium hydride, lithium hydride, potassium hydride,rubidium hydride, cesium hydride, magnesium hydride, calcium hydride,and combinations thereof.
 3. The method according to claim 1 whereinsaid ether is of purity greater than about 90%.
 4. The method accordingto claim 1 wherein said halide has the formula RX, where R is an alkyl,alkenyl, alkynyl, substituted heterocycle, unsubstituted heterocycle,substituted phenyl, or unsubstituted phenyl, having 1 to 20 carbon atomsand where X is a halogen.
 5. The method according to claim 1, whereinsaid ether is an alkyl ether of tetrahydrofurfuryl alcohol, said alkylcomprising 1 to 22 carbon atoms.
 6. The method according to claim 1wherein said ether is di-tetrahydrofurfuryl ether.
 7. The methodaccording to claim 1, wherein said low work function element iselemental sodium metal or sodium hydride.
 8. The method according toclaim 1, wherein said low work function metal is a reducing agent.